title: Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease.
abstract: Mice with homozygous null mutations in the HDL receptor (scavenger receptor class B, type I, or SR-BI) and apolipoprotein E (apoE) genes [SR-BI/apoE double KO (SR-BI(-/-)/apoE(-/-) or dKO) mice] spontaneously develop occlusive, atherosclerotic coronary artery disease (CAD) and die prematurely (50% mortality at 42 d of age). Using microarray mRNA expression profiling, we identified genes whose expression in the hearts of dKO mice changed substantially during disease progression [at 21 d of age (no CAD), 31 d of age (small myocardial infarctions), and 43 d of age (extensive myocardial infarctions) vs. CAD-free SR-BI(+/-)/apoE(-/-) controls]. Expression of most genes that increased >sixfold in dKO hearts at 43 d also increased after coronary artery ligation. We examined the influence and potential mechanism of action of apolipoprotein D (apoD) whose expression in dKO hearts increased 80-fold by 43 d. Analysis of ischemia/reperfusion-induced myocardial infarction in both apoD KO mice and wild-type mice with abnormally high plasma levels of apoD (adenovirus-mediated hepatic overexpression) established that apoD reduces myocardial infarction. There was a correlation of apoD's ability to protect primary cultured rat cardiomyocytes from hypoxia/reoxygenation injury with its potent ability to inhibit oxidation in a standard antioxidation assay in vitro. We conclude that dKO mice represent a useful mouse model of CAD and apoD may be part of an intrinsic cardioprotective system, possibly as a consequence of its antioxidation activity.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Tsukamoto
authors.forename: D R
authors.initials: DR
authors.lastname: Mani
authors.forename: Jianru
authors.initials: J
authors.lastname: Shi
authors.forename: Songwen
authors.initials: S
authors.lastname: Zhang
authors.forename: Darrow E
authors.initials: DE
authors.lastname: Haagensen
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Otsuka
authors.forename: Jian
authors.initials: J
authors.lastname: Guan
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Smith
authors.forename: Wei
authors.initials: W
authors.lastname: Weng
authors.forename: Ronglih
authors.initials: R
authors.lastname: Liao
authors.forename: Frank D
authors.initials: FD
authors.lastname: Kolodgie
authors.forename: Renu
authors.initials: R
authors.lastname: Virmani
authors.forename: Monty
authors.initials: M
authors.lastname: Krieger
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D053399:Apolipoproteins D / Q000097:blood* / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000097:blood* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000235:genetics / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D017208:Rats, Wistar; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D053399:Apolipoproteins D; D001057:Apolipoproteins E; C454739:Scarb1 protein, mouse; C495125:Scarb1 protein, rat; D051122:Scavenger Receptors, Class B
keywords: antioxidant; lipocalin